Recent evidence suggests that the epsilon isoform of protein kinase C (PKCepsilon) plays a critical role in ethanol-seeking behavior. We recently demonstrated that mice lacking PKCepsilon and consume 50-75% less ethanol than their wildtype counterparts in two separate self-administration paradigms. We also demonstrated that PKCepsilon null mutant mice demonstrate reduced ethanol intake following deprivation (a model of relapse), reduced ethanol withdrawal severity, and a lack of ethanol-stimulated mesolimbic dopamine release. These data suggest that selective pharmacological inhibition of PKCepsilon activity may be a novel therapeutic avenue for the treatment of various aspects of alcoholism. However, given the high degree of structural homology between PKC isoforms, to date there are no specific CNS-penetrant pharmacological compounds that selectively inhibit PKC activity. An alternative approach to directly inhibiting PKCepsilon activity is to pharmacologically modulate a specific neurotransmitter receptor system that is directly coupled to PKCepsilon. Our preliminary data show that the type 5 metabotropic glutamate receptor (mGluR5) may be functionally linked to PKCepsilon activity. We show that the selective mGluR5 antagonist MPEP reduces ethanol self-administration and enhances ethanol-stimulated locomotor activity in a PKCepsilon-dependent manner. We also show that PKCepsilon and mGluR5 immunoreactivity are highly co-localized in brain regions known to be involved in ethanol consumption and reinforcement. Finally, MPEP reduces the rewarding effects of ethanol as measured by the conditioned place preference paradigms. Taken together, these data indicate that the mGluR5 receptor may be functionally coupled to PKCepsilon, and that selective mGluR5 antagonists may be useful in treating excessive alcohol consumption, relapse following detoxification, and withdrawal symptom severity. The following Specific Aims describe preclinical experiments designed to investigate the functional coupling between mGluR5 and PKCepsilon, and to evaluate the ability of mGluR5 antagonists to reduce ethanol-stimulated mesolimbic dopamine release, relapse to drinking following deprivation, and withdrawal severity. The first specific aim will be to biochemically characterize the functional coupling between the mGluR5 receptor and PKCepsilon activity. The second specific aim will determine if mGluR5 antagonists inhibit ethanol-stimulated mesolimbic dopamine release, a phenomenon thought to contribute to the reinforcing properties of ethanol. The third specific aim will determine if mGluR5 antagonists reduce relapse to ethanol self-administration following deprivation in both wildtype and PKCepsilon null mutant mice. Finally, the fourth specific aim will determine if mGluR5 antagonism attenuates ethanol withdrawal severity in both wildtype and PKCepsilon null mutant mice. Together, these proposed preclinical studies will attempt to delineate a novel pharmacological target that may be used to treat various aspects of alcohol abuse and alcoholism.